Sudden cardiac death due to ventricular fibrillation kills over 400,000 persons annually in the United States. Significant progress has been made toward understanding this arrhythmia and many patients can now be implanted with internal defibrillators designed to detect and correct fibrillation within ten to thirty seconds, although thresholds are high. Biphasic waveforms, in which the polarity is reversed partway through the pulse, can reduce defibrillation threshold. However, they can also increase threshold depending on the relative amplitude and duration of the two phases. Both mechanisms underlying defibrillation and those underlying threshold alteration with biphasic waveforms remain almost completely unknown. The optimal shape for biphasic waveforms also remains unknown. The long-term objective of this project is to improve efficacy of cardiac defibrillation by alteration of the electric waveform. The over-all goals of this competing continuation are to: 1) determine mechanisms underlying threshold reduction with long and short duration biphasic waveforms and the effect of electrode configuration on these mechanisms, and 2) develop a method for predicting defibrillation threshold in individual patients. This method will involve a 3-dimensional mesh plot of monophasic action potential duration as a function of stimulus coupling interval and local stimulus intensity, in combination with local fractionation produced by shocks given in sinus rhythm. The underlying hypothesis is that the electric shock defibrillates by differing mechanisms depending on the waveform. Monophasic waveforms and long duration biphasic waveforms prolong cellular refractory period so that fibrillation wavefronts encounter refractory tissue and die out, causing fibrillation to halt. In contrast, short duration biphasic waveforms both prevent transient dysfunction in high current density regions near the electrodes and prevent dispersion of refractoriness leading to refibrillation by inhibiting action potential prolongation in regions of higher current intensity. We also hypothesize that successful defibrillation is dependent on the "average current" of each phase, rather than waveform "tilt". These hypotheses will be tested using monophasic action potential recordings from different regions of the ventricle in the isolated rabbit heart, a model which we have previously used for several fibrillation/defibrillation studies. The fundamental knowledge produced by these studies will lead to a greater understanding of defibrillation mechanisms and produce improved waveforms to allow development of new smaller, safer implantable defibrillators. New testing algorhythmis will also allow defibrillator testing without inducing very risky multiple fibrillation/defibrillation episodes.